Polymeric drug delivery systems (DDSs) can change the pharmacokinetics of chemotherapeutic drugs, focusing their action on the tumor site. For DDSs made out of block copolymers these features are directly influenced by the structure of the two interfaces present in the block copolymers: the hydrophilic-hydrophobic interface and the interface between the chemically stable and the biodegradable polymeric blocks. The two interfaces coincide in conventional PEG-based amphiphilic diblock copolymers, which make them susceptible to hydrolysis and premature degradation by amphiphilic esterases, resulting in a dramatic decrease of their circulation time in vivo. Our long-term goal is to enhance the shelf stability, in vivo dynamic selective stability and circulation time, drug protection and to control drug loading and drug release profile of polymeric DDSs via interfacial engineering of the PEG-based amphiphilic copolymers. The overall objective of this proposal is to test the above-mentioned properties of a set of PEG-PBO-PCL block copolymers with tuned interfaces via insertion of a hydrolytically stable hydrophobic PBO linker in between the PEG and PCL blocks. Our central hypothesis is that the PBO block separates the two interfaces, limits access of hydrolytic enzymes to the biodegradable hydrophobic core of the DDS, enhances drug loading and release profiles of the carrier and provides selective stability against esterases in blood/tumor. The rationale is that knowledge on how separation of the two interfaces affects the main features of these DDSs will allow generation of polymeric DDSs with pre-programmed stability, loading and release parameters. The specific aims of this project are: Specific Aim 1: To evaluate the impact of interfacial engineering via a hydrolytically stable hydrophobic PBO linker of various lengths on the physicochemical properties, shelf life and hydrolytic stability of polymeric nanoparticles against esterases present in blood and in tumors (selective stability) generated from engineered PEG-PBO-PCL triblock copolymers of various sizes in comparison with PEG-PCL diblocks as control standards. Specific Aim 2: To assess the impact of the nature and length of non-hydrolyzable PBO hydrophobic linker on chemotherapeutic drug docetaxel loading and release profile, toxicity and circulation time of engineered PEG-PBO-PCL triblock copolymers of various sizes in comparison with PEG-PCL diblocks, in vitro and in vivo, using animal models of breast cancer. In our opinion the proposed research is innovative because separating the two interfaces will increase the resilience of the polymeric material and its self- assemblies in blood following systemic delivery, will improve circulation time and shelf stability of DDS, and will efficiently modulate its drug loading and release properties. This contribution will be significant because it may lead to the development of DDSs with enhanced circulation time and selective in vivo stability, suitable for targeting, with enhanced shelf stability and improved drug loading/release and toxicity profiles.